Alzheimer's disease (AD) is the most common form of dementia, affecting an estimated 27 million people worldwide in 2006. Age is the greatest known risk factor for AD with an incidence of 25-50% in people aged 85 years or older. As the average age of the population increases, the number of patients with AD is expected to rise exponentially. AD is the fifth leading cause of death in people aged 65 and older, and most patients eventually need nursing home care. Consequently, AD has an enormous economic impact, e.g., estimated direct and indirect costs for 2005 in the US only were $148 billion. Besides the economic costs, AD has a devastating impact upon patients and their family members, causing severe emotional distress and turmoil.
Patients are diagnosed with probable AD based on the presence of dementia with progressive worsening of memory and other cognitive functions and with the exclusion of other causes of dementia. A diagnosis of AD can only be confirmed post-mortem as the clinical diagnosis is based on brain neuropathology, specifically, the diagnosis requires an evaluation of brain tissue, including the existence and concentration of extracellular plaques in the brain, intracellular tangles, and brain neurodegeneration. Dementia is also a required part of the diagnosis, since plaques and tangles are observed in cognitively normal adults, although usually to a lesser extent.
Two classes of medications, cholinesterase inhibitors and an N-methyl-D-aspartic acid (NMDA) antagonist, are currently approved for AD. Although these two classes of therapeutics show some clinical benefit, many patients do not respond, and these drugs only ameliorate the symptoms of AD (e.g., cognitive function) with little or no modification of disease progression. For these reasons, identification of disease-modifying therapeutics for this devastating disease is a major focus of the pharmaceutical industry.
Microtubule stabilizers have been suggested as therapies to treat tauopathies including AD. See, e.g., Lee et al. (references list, infra). In U.S. Pat. No. 5,580,898, filed May 1994 and granted Dec. 3, 1996, Trojanowski et al. suggest use of paclitaxel (TAXOL®) to treat AD patients by stabilizing microtubules. Paclitaxel has proven highly effective as a microtubule-stabilizing agent in treating cancer patients; however, it presents brain-penetration and peripheral neuropathy issues when considered for AD (further described below), and has not emerged as a viable therapy to treat AD.
In 1995, epothilone B was reported to exert microtubule-stabilizing effects similar to paclitaxel (Bollag et al. 1995). Epothilone A and epothilone B are naturally-occurring compounds that were isolated by Hofle et al. from fermentation products of the microorganism Sorangium cellulosum (e.g., WO 93/10121). Hofle et al. also discovered 37 natural epothilone variants and related compounds produced by S. cellulosum and modified strains, including epothilones C, D, E, F and other isomers and variants (e.g., U.S. Pat. No. 6,624,310).
Unique characteristics of the natural epothilones generated much interest in their exploration as potential anti-cancer drugs. Now, nearly twenty years have passed since the first discovery of the natural epothilones A and B. Hundreds of epothilone analogs have been discovered and described in various patent applications, and abundant literature has published under the rubric, “epothilones” (See, e.g., Altmann et al., references list, infra, at 396-423).
The assignee of the current application has developed ixabepilone, a semi-synthetic analog of epothilone B, for treatment of cancer. Ixabepilone has the structural formula:

The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione. See also U.S. Pat. No. 6,605,599, assigned to the current assignee, Bristol-Myers Squibb Company (BMS). Ixabepilone is a microtubule-stabilizing agent that has been approved by the FDA for treatment of metastatic breast cancer and is sold by BMS under the tradename IXEMPRA®. Ixabepilone can be prepared as described in U.S. Pat. No. 6,605,599 or 7,172,884, incorporated herein by reference.
Other natural epothilones and analogs are in advanced clinical trials for treatment of cancer including epothilone B (a/k/a patupilone, or EPO-906), in Phase III trials by Novartis Pharma AG, for treatment of ovarian cancer, and sagopilone (or ZK-EPO), a benzothiazolyl-7-propenyl synthetic analog of epothilone B, in Phase II trials by Bayer Schering AG for treatment of various cancers including tumors of the ovary, breast, lung, prostate and melanoma. In 2007, a Phase II trial with sagopilone was initiated in the US for treatment of brain metastases from breast cancer. Additionally, an epothilone D analog, KOS-1584, had advanced to Phase II clinical trials by Kosan Biosciences, Inc. (now a wholly-owned subsidiary of BMS) for treatment of non-small-cell lung cancer and solid tumors, and epothilone D had advanced to Phase II clinical trials for treatment of cancer by Kosan in collaboration with Hoffmann-La Roche, Inc.; however, the clinical trials with epothilone D for treating cancer were discontinued in 2007. The structure for epothilone D can be represented by the following formula:

The epothilone D compound is claimed, as composition of matter, in U.S. patent application Ser. No. 09/313,524 to Hofle et al., and described in U.S. Pat. Nos. 6,242,469 and 6,284,781 to Danishefsky et al., which application and patents were the subject of Interference No. 105,298, before the USPTO Board of Patent Appeals and Interferences.
The assignee of the current application also has clinically evaluated BMS-310705 (Compound II herein), for cancer therapy. BMS-310705 was pursued through Phase I clinical trials for treatment of ovarian cancer; it is an amino-epothilone F analog and has the chemical structure:

Compound II (BMS 310705) can be prepared as described in U.S. Pat. No. 6,262,094, incorporated herein.
While certain of the epothilone compounds and analogs have been clinically evaluated for treating cancers, it is highly unpredictable whether a cancer drug may be effectively used to treat neurodegenerative diseases including AD. There are various factors affecting this unpredictability. One factor is the substantial difficulty of achieving good brain penetration due to the blood-brain barrier (BBB). For a compound to be useful in treating neurodegenerative brain diseases, it is necessary that the compound cross the BBB; however, since a function of the BBB is to protect the brain from external substances and toxins, discovering a useful drug that has good BBB penetration is challenging. Additionally, BBB penetration is an undesirable feature for a cancer drug (other than brain cancer drugs). With a cancer drug, BBB penetration is usually sought to be avoided, whereas for a drug designed to treat AD or other neurodegenerative brain diseases, good BBB penetration is necessary for the compound to be effective. Thus, for example, while paclitaxel is a highly-successful cancer drug, it has not emerged as a useful therapy to treat brain diseases such as AD, as it has a low rate of brain penetration through the BBB.
Further factors affecting the unpredictability of evaluating the usefulness of cancer drugs, particularly microtubule-stabilizing drugs, in treating AD and other brain diseases involve the ability of a drug to penetrate the brain, to be retained in the brain for long periods, and to selectively accumulate in the brain relative to peripheral tissues. These parameters can be measured using brain-to plasma ratios, brain half-life, and the ratio of the amount of drug retained in the brain as compared with peripheral tissues (most particularly the liver). Additionally, measuring brain penetration, retention and selective brain accumulation with microtubule-stabilizers is complex because these compounds are typically rapidly cleared from plasma but more slowly cleared from microtubule-containing tissues, making it important to set appropriate time windows for comparisons of plasma and tissue levels. The brain-to-peripheral-tissue ratio is a particularly important measurement given that microtubule-stabilizing agents at certain doses are highly cytotoxic to peripheral tissues: when microtubule-stabilizing agents, such as paclitaxel, are administered at chemotherapeutic doses, a peripheral neuropathy and other side effects often occur (Postma et al. 1999). These side effects may be tolerable in treating cancer patients but a different therapeutic window and acceptable side-effect profile exists in treating patients suffering from AD and other brain diseases.
Yet further challenges involved with looking to cancer drugs for potential application to neurodegenerative diseases involve the mode of administration and the bioavailability and cytotoxicity associated therewith.
In WO 2005/075023 A1, published Jan. 30, 2004, to Andrieux et al. of INSERM, it is suggested that certain epothilones and analogs including epothilone A, B, C, D, E, and F, and benzothiazolyl and pyridyl epothilone B and D analogs may be useful in treating diseases involving a neuronal connectivity defect, such as schizophrenia or autism. However, Andrieux et al. disclaimed and thereby taught against use of these compounds for treating AD, stating that diseases associated with neuronal connectivity defects (i.e., those claimed in that application) “are different from progressive dementing disorders like Alzheimer, which involve neuronal degeneration.”
In WO 03/074053 ('053), to Lichtner et al. of Schering AG (published Sep. 12, 2003), there is a broad claim to use of a broad genus of epothilone compounds and synthetic analogs for treating brain cancer and other brain diseases, including primary brain tumor, secondary brain tumor, multiple sclerosis, and AD. Lichtner et al. report certain data on four compounds, namely, paclitaxel as compared with the compounds named therein as compound 1: 4,8-dihydroxy-16-(1-methyl-2-(2-methyl-4-thiazolyl)-ethenyl)-1-oxa-7-(1-propyl)-5,5,9,13-tetramethyl-cyclohexadec-13-ene-2,6-dione; compound 2: dihydroxy-3-(1-methyl-2-(2-methyl-4-thiazolyl)-ethenyl)-10-propyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione; and compound 3: 7,11-dihydroxy-3-(2-methylbenzothioazol-5-yl)-10-(prop-2-en-1-yl)-8,8,12,16-tetramethyl-4,17-diooxabicyclo[14.1.0]heptadecane-5,9-dione (see WO '053 publication at page 21).
Notably, Lichtner et al. report brain and plasma concentration data for the above three epothilone analogs, but only for periods of up to 40 minutes. Lichtner et al. are not able to report comparative data against paclitaxel on brain-to-plasma levels because their paclitaxel brain levels were below the level of detection, and they do not report data relating to brain-to-liver ratios, half-life, or brain retention for any of the compounds (e.g., concentration of drug in brain tissue over extended periods of time).
In view of the foregoing, there remains a need in the art for methods of treating tauopathies, particularly Alzheimer's disease.